The goal of this K0I application is the help the candidate develop as an independent, interdisciplinary investigator with expertise on vulnerability to a major public health concern: Major Depressive Disorder (MDD). Although research has demonstrated MDD to be heritable to a substantial extent and to share genetic heritability with trait negative affect (one vulnerability factor to MDD), the etiology of MDD requires further study. Accumulating evidence suggests that acetylcholine neurotransmission may play a role in the neurobiology of MDD. Thus, it is conceivable that molecular variation in genes regulating cholinergic function may modulate risk for MDD, depressive symptomatology, and trait negative affect. As part of the proposed training, the candidate will develop further expertise in MDD-related psychoneurophysiological phenotypes and molecular genetics, which will build upon her prior training in clinical psychology and behavioral medicine, and preliminary research in molecular genetics. The applicant's preliminary work documents an initial association between genetic variation in one component of the acetylcholine system (i.e., the choline transporter) and psychometrically assessed depressive symptoms. The potential functional significance of this sequence variation is also documented with respect to an "in vivo" peripheral index of cholinergic activity measuring autonomic cardiac function. The proposed training activities will be directly applied to conduct a research study in the context of a funded research project at the University of Pittsburgh. The candidate proposes to confirm and extend prior research on the role of acetylcholine neurotransmission in MDD by investigating known genetic variation of relevance to acetylcholine neurotransmission (e.g., synthesis, release, receptor activation, or enzymatic degradation) in association with psychoneurophysiological phenotypes of relevance to MDD (i.e., presence or absence of a lifetime history of MDD, depressive symptoms, trait negative affect, and autonomic cardiac regulation) in a community sample of 1200 men and women. The findings from the proposed research will serve as preliminary support for an R01 application to confirm and extend these results using more definitive genetic designs. Ideally, as part of an interdisciplinary, collaborative research group, such a study will examine psychoneurobiologic, quantitative endophenotypes in extended pedigrees (relatives of probands with major depression) and unaffected, control samples. This training will help to improve our understanding of heritable vulnerability to MDD as well as provide the candidate with exceptional training in MDD-related quantitative phenotypes and molecular genetics. [unreadable] [unreadable]